This is a second revision of an Investigator-Initiated Exploratory/Developmental Research (R21) grant application to the National Center for Complementary and Alternative Medicine to explore the use of polyunsaturated fatty acids (PUFAs) as an augmentation strategy for the treatment of unipolar major depression. Major depression is a common mental disorder, and is associated with serious functional impairment, morbidity and mortality. Moreover, it also produces a significant financial burden on our society. Despite the availability of numerous pharmacologic and psychotherapeutic interventions, the current treatment of depression is not optimal. Even in patients who do respond to treatment, remission is rarely complete. In addition, the onset of action of antidepressants is delayed; the drugs usually must be taken for three weeks or more before improvement is clinically discernible. Accordingly, a number of augmentation strategies to hasten the onset of activity and increase the efficacy of traditional antidepressants have been proposed and tested, but many of these produce significant side-effects, and some patients still do not respond. PUFAs are found in high concentrations in the central nervous system, and they appear to be involved in many aspects of signal transduction. Recently, evidence has surfaced suggesting that the dietary intake of PUFAs might be related to depression, and the administration of PUFAs might reduce depressive symptomatology. In this application, we propose testing the hypothesis that administration of one of the PUFAs, eicosapentanoic acid (EPA), in combination with a selective serotonin reuptake inhibitor (SSRI) antidepressant will improve treatment outcome in unipolar major depression. In addition, we will determine whether the onset of antidepressant activity occurs more rapidly when EPA supplementation is combined with selective serotonin uptake inhibitor. The results of the proposed study might provide a new, economical, safe, and potentially important alternative approach to the treatment of unipolar major depression.